OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pontes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 ± 48 ms vs. drug: 391 ± 60, p = NS) whereas during SR, QT was prolonged from 405 ± 55 to 470 ± 67 ms (p <0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although AQT was greater in group I during SR (91 ± 22 vs. 45 ± 25 ms, p <0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 ± 0.96 vs. 2.77 ± 0.25 ng/ml), and in AF (2.76 ± 1.22 ng/ml). ΔQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p <0.05), and QT dispersion developing during the infusion (r = 0.79, p <0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response.